Original Article

Development of β-amino-carbonyl compounds as androgen receptor antagonists

Authors: Zhi-yun Zhang, Yan-hui Zhu, Cai-hong Zhou, Qing Liu, Hui-li Lu, Yun-jun Ge, Ming-wei Wang
DOI: 10.1038/aps.2013.201


Zhi-yun ZHANG1, #, Yan-hui ZHU1, #, Cai-hong ZHOU1, Qing LIU1, Hui-li LU1, Yun-jun GE1, Ming-wei WANG1, 2, *
1The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China; 2School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China

Aim: Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel β-amino-carbonyl-based androgen receptor antagonist.
Methods: Different isomers of the β-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.

Results: Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21–1 and 21–2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012–4 (1R, 3S).

Conclusion: Compound 6012–4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo.

Keywords: chemerin; CMKLR1; GPCR; receptor trafficking; receptor internalization; endocytosis; calcium flux; ERK phosphorylation

We are indebted to Ms Xiao-yan WU for technical assistance. This work was partially supported by grants from the Ministry of Health (2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, and 2013ZX09507002), Shanghai Science and Technology Development Fund (13DZ2290300) and Thousand Talents Program in China.
# These two authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail mwwang@simm.ac.cn
Received 2013-10-17 Accepted 2013-12-18

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